The use of narcotic analgesics to treat severe chronic orofacial pain conditions is limited by potentially serious side-effects. Kappa (kappa opioid drugs have fewer clinically limiting adverse effects than other narcotics (notably including much lower abuse potential), but candidate drugs have proved disappointing in clinical trials, due largely to their poor analgesic efficacy. Preliminary work in our laboratory has revealed that one of the most important limits on analgesic efficacy of kappa opioid drugs in clinical orofacial pain is their activation of a distinct anti-analgesic mechanism that opposes their analgesic effect. This anti-analgesic effect is strongly sex-dependent, causing males to experience a net increase in pain when administered kappa opioids, while females experience potent dose-dependent analgesia similar in magnitude to that induced by high-dose morphine. We propose a series of studies to assess the impact of the anti-analgesia mechanism on kappa opioid analgesic efficacy in chronic orofacial pain syndromes. Successful future use of kappa opioid analgesic drugs in orofacial pain syndromes will likely depend on therapeutic strategies designed to minimize their antianalgesic effect. Achieving this goal will require a deeper understanding of the mechanisms of kappa opioid anti-analgesia, and therefore, we will also investigate receptor pharmacology of the anti-analgesia circuitry in a clinical model of orofacial pain. Consistent with the stated goals of RFA-DE-07-006, our proposal will employ clinical studies of patients with chronic and acute painful orofacial disorders to provide important insights into the biological mechanisms underlying analgesic treatment of chronic orofacial pain. These studies will involve the efforts of a multidisciplinary research team that will include expertise in clinical orofacial pain practice, human drug studies in orofacial pain, computational pharmacology, and receptor binding biochemistry. Our observations are likely to directly impact clinical strategies to improve the efficacy of analgesic therapy in chronic orofacial pain conditions, and eliminate gender differences in therapeutic efficacy.